The present invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives. Preferably, the present invention relates to an improved process for preparing indane carboxylates and cyclopentano[b]pyridine derivatives. Advantageously, the present invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-(2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof. Such compounds are described in International Application Number: PCT/US94/04603xe2x80x94International Publication Number WO 94/25013 published on Nov. 10, 1994 and in U.S. Pat. No. 5,389,620, as being useful as endothelin receptor antagonists. Also invented are novel intermediates useful in preparing these compounds.
Processes for the preparation of indane carboxylates, specifically (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-prop-1-yloxy)indane-2-carboxylic acid and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid have previously been described. In particular a multistep process to prepare (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in 6% overall yield (not including a racemic separation step) from methyl 3-(prop-1-yloxy)benzoylacetate and a multistep process to prepare (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl[-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in 2% overall yield (not including a racemic separation step) from methyl 3-(prop-1-yloxy)benzoylacetate is reported in International Publication Number WO 94/25013, published Nov. 10, 1994. The syntheses of these molecules are complicated by the presence of three chiral centers in each compound.
Processes for the preparation of cyclopentano[b]pyridine derivatives have previously been described. In particular, multistep processes to prepare cyclopentano[b]pyridine derivatives, in low over all yield, are reported in U.S. Pat. No. 5,389,620.
Thus, there is a need in the art for an economical method to prepare indane carboxylates and cyclopentano[b]pyridine derivatives, specifically (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof.
The numerous advantages of the presently invented process and intermediates will become apparent upon review of the following description.
This invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives.
This invention also relates to novel intermediates useful in preparing aromatic ring-fused cyclopentane derivatives.
This invention relates to an improved process for preparing indane carboxylates.
This invention also relates to novel intermediates useful in preparing indane carboxylates.
This invention relates to an improved process for preparing cyclopentano[b]pyridine derivatives.
This invention also relates to novel intermediates useful in preparing cyclopentano[b]pyridine derivatives.
This invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the ethylene diamine 2:1 salt.
This invention relates to novel intermediates useful in preparing (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
This invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the disodium salt.
This invention relates to novel intermediates useful in preparing (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
Unless otherwise defined, the term xe2x80x98aromatic ring-fused cyclopentane derivativesxe2x80x99 as used herein, is meant the racemic compounds of Formula (1): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom;
R1 is 
xe2x80x83where R3 and R4 are independently H, OH, C1-8alkoxy, F, CF3 or C1-6alkyl and R5 is xe2x80x94OCH2CO2H or xe2x80x94OCH2CH2OH;
R2 is 
xe2x80x83where R3 and R4 are as indicated above and
Z is H, OH, or C1-5alkoxy;
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (1) are the compounds of Formula (17): 
wherein A, B, C, D, R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
By the term indane carboxylates as used herein is meant the racemic compounds of Formula (2): 
wherein R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (2) are the compounds of Formula (18): 
wherein R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
By the term cyclopentano[b]pyridine derivatives as used herein is meant the racemic compounds of Formula (3): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and
R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (3) are the compounds of Formula (19): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and
R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
In Formula (3) compounds, in Formula (19) compounds and in Formula (1) compounds when one of A, B, C or D is a nitrogen atom, preferably A is nitrogen.
Pharmaceutically acceptable salts of the compounds of Formulas (1), (2), (3), (17), (18) and (19) are formed where appropriate by methods well known to those of skill in the art.
Pharmaceutically acceptable salts of (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid are formed where appropriate by methods well known to those of skill in the art.
By the term xe2x80x9cPrxe2x80x9d as used herein is meant n-propyl.
By the term xe2x80x9cPhxe2x80x9d as used herein is meant phenyl.
As used in the specification and in the claims, unless otherwise defined, the term Xc means a chiral auxiliary. By the term xe2x80x9cchiral auxiliaryxe2x80x9d as used herein is meant a non-racemic functional group that imparts a diastereoselective reaction at a remote prochiral center of a molecule. Chiral auxiliaries as used herein are formed by reaction with a compound of the formula HXc wherein Xc is as described above. Examples of HXc as used herein include: 8-phenylmenthol (such as described in D. Comins et al. J. Org. Chem., vol. 58, 4656 (1993)), N-substituted borane-2, 10-sultams (such as described in W. Oppolzer J. Am. Chem. Soc., 112 2767 (1990)), preferably, 4-substituted or 4,5-substituted 2-oxazolidinones derived from amino acid derivatives such as phenylglycinol or valinol (such as described in D. Evans et al. J. Am. Chem. Soc., 109, 6881 (1987) and in D. Evans et al. Tet. Lett., 28, 1123 (1990)) and, most preferably, 4-substituted or 4,5-substituted 2-imidazolidinones derived from compounds such as ephedrine (such as described in S. E. Drewes, et al. Chem. Ber., 126, 2663 (1993)). The most preferred xe2x80x9cXc xe2x80x9d for use herein is the predominately optically pure substituent of the formula 
Thus, the most preferred form of a chiral auxiliary for use herein is a compound of formula (u): 
Additionally, the racemic compounds of Formulas (1), (2) and (3) are prepared as described herein by substituting the chiral Xc substituent, as used herein, with an a chiral group, such as an alkoxy or amine group.
The term xe2x80x98activation reactionxe2x80x99 for use herein refers to the numerous reactions and reaction conditions known to those skilled in the art to effect the introduction of a Br, I, xe2x80x94OSO2CF3 or a xe2x80x94OSO2F substituent.
The term (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid as used herein utilizes standard chemical terminology and refers to Compound (r) 
The term (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid ethylene diamine salt (2:1) as used herein utilizes standard chemical terminology and refers to Compound (s) 
The term (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid as used herein utilizes standard chemical terminology and refers to Compound (j) 
The term (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt as used herein utilizes standard chemical terminology and refers to Compound (k) 
The indane carboxylates of Formula (18) of the current invention are prepared by methods outlined in the Schemes below and in the Examples from compounds of Formula (a); 
where R is H, OH, C1-5alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy. Compounds of Formula (a) are known or can be prepared from readily available starting materials by those skilled in the art.
By the term xe2x80x98protected oxy groupxe2x80x99 and xe2x80x98protected OHxe2x80x99 as used herein, is meant any conventional blocking group in the art such as described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by Theodora W. Greene. Wiley-Interscience, 1981, New York, provided that such protected oxy groups or such protected OH do not include moieties that render inoperative the presently invented process. A preferred protected oxy group for use herein is benzyloxy. A preferred protected OH for use herein is benzyloxy.
Further, when necessary or desired, R can be converted to a substituent of Z. Reactions to convert R to Z are performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in these synthetic pathways. For example, hydroxyl groups can be converted into C1-5alkoxy groups by alkylation. Protected oxy groups can be deprotected and further reacted to form a substituent of Z.
The present invention provides an improved process for the production of indane carboxylates of Formula (18) as indicated in Schemes 1 and 2 below. 
Scheme 1 outlines formation of indane carboxylates wherein R5 is xe2x80x94OCH2CO2H, preferably the disodium salt, Compound (k). As used in Scheme 1, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F. Compounds of Formula (c) are prepared in one or more steps by treating a compound of Formula (a) in an activation reaction, preferably with bromine in methylene chloride, to introduce substituent R7. Compounds of Formula (d) are prepared by reacting a compound of Formula (c) with an acid chloride, such as thionyl chloride, and using this product as an acylating agent in a reaction, such as a Grignard reaction with a compound of Formula (t) as defined on page 32, or a Friedel-Crafts reaction, such as described in Example 1, step (iii). Compounds of Formula (e) are prepared by reacting a compound of Formula (d) with a chiral auxiliary in the presence of palladium(II) acetate/triphenylphosphine catalyst. Treatment of a compound of Formula (e) with an appropriately substituted 3,4-(methylenedioxy)phenylmagnesium bromide (which can be readily prepared from commercially available starting materials) and a copper complex, such as copper(I) bromide-dimethylsulfide complex (which is commercially available from the Aldrich Chemical Co. of Milwaukee, Wis.), in tetrahydrofuran followed by crystallization gives compounds of Formula (f) as the predominately pure diastereomer. Treatment of a compound of Formula (f) with sodium methoxide/methanol gives compounds of Formula (g). Compounds of Formula (h) are prepared by treating a compound of Formula (g) in methanol with anhydrous acid. Compounds of Formula (i) are prepared by hydrogenating a compound of Formula (h) over palladium on carbon. Treating a compound of Formula (i) with methyl bromoacetate and potassium carbonate in acetone/methanol, followed by saponification/epimerization effected with lithium hydroxide monohydrate and acid workup yields the corresponding diacid of Formula (6) (preferably Compound (j) as used herein). Compounds of Formula (6) are treated with sodium hydroxide to give compounds of Formula (4) (preferably Compound (k) as used herein). Additionally, treating a compound of Formula (i) with ethylene carbonate/potassium carbonate in toluene at 90-115xc2x0 C. followed by saponification/epimerization with lithium hydroxide and acidic work up is a preferred method for preparing a compound of Formula (7). It is readily apparent to those of skill in the art that the substituent xe2x80x94OCH2Ph in the above Scheme is functioning as a protected OH and that another protected OH group could be utilized in its place or that, under appropriate circumstances, the unprotected OH could be utilized. 
Scheme 2 outlines formation of indane carboxylates wherein R5 is xe2x80x94OCH2CH2OH, preferably the ethylene diamine salt (2:1), Compound (s). As used in Scheme 2, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F. The acid chloride of the compounds of Formula (c) from Scheme 1 are reacted in an acylation reaction, preferably in a Grignard reaction with a compound of Formula (v) prepared as described on page 33, to give compounds of Formula (l). Compounds of Formula (m) are prepared by reacting a compound of Formula (l) with a chiral auxiliary in the presence of palladium(II) acetate/triphenylphosphine catalyst. Treatment of a compound of Formula (m) with an appropriately substituted 3,4-(methylenedioxy)phenylmagnesium bromide (which can be readily prepared from commercially available starting materials) and a copper complex, preferably a copper (I) salt such as CuCl, CuBr, CuCN or most preferably copper(I) bromide-dimethylsulfide complex (which is commercially available from the Aldrich Chemical Co. of Milwaukee, Wis.) in tetrahydrofuran gives compounds of Formula (n) as the predominately pure diastereomer. Treatment of a compound of Formula (n) with sodium methoxide/methanol gives compounds of Formula (o). Compounds of Formula (p) are prepared by treating a compound of Formula (o) in methanol with anhydrous acid. Compounds of Formula (q) are prepared by hydrogenating compounds of Formula (p) over palladium on carbon. Treatment of compounds of Formula (q) with lithium hydroxide monohydrate followed by acidic workup gives the acid of Formula (7) (preferably Compound (r) as used herein). Compounds of Formula (7) are treated with ethylene diamine to give compound of Formula (8) (preferably Compound (s) as used herein). It is readily apparent to those of skill in the art that the substituent xe2x80x94OCH2Ph in the above Scheme is functioning as a protected OH and that another protected OH group could be utilized in its place or that, under appropriate circumstances, the unprotected OH could be utilized.
The racemic compounds of Formulas (1), (2) and (3) are prepared according to the methods outlined in Schemes (1) and (2) and in the Examples by substituting a compound of Formula (9): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom and
R is H, OH, C1-5alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy,
for the compound of Formula (a) and by substituting the chiral Xc substituent of the chiral auxiliary with an a chiral group, such as an alkoxy or amine group.
Compounds of Formula (9) are known or can be prepared from readily available starting materials by those skilled in the art.
Thus, an a chiral group is substituted for the Xc substituent of the chiral auxiliary in Schemes 1 and 2 to prepare compounds of Formula (2) and intermediates useful in preparing compounds of Formula (2). The compounds of Formula (9) are utilized in Schemes 1 and 2, by substituting the chiral Xc substituent of the chiral auxiliary with an a chiral group, to prepare compounds of Formula (1) and intermediates useful in preparing compounds of Formula (1). The compounds of Formula (9), wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, are utilized in Schemes 1 and 2, by substituting the chiral Xc substituent of the chiral auxiliary with an a chiral group, to prepare compounds of Formula (3) and intermediates useful in preparing compounds of formula (3).
The cyclopentano[b]pyridine derivatives of Formula (19) of the current invention are prepared according the methods outlined in Schemes 1 and 2 and in the Examples from compounds of Formula (9) wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom. Preferred among Formula (9) compounds when a nitrogen is present are those wherein A is nitrogen.
The aromatic ring-fused cyclopentane derivatives of Formula (17) of the current invention are prepared according the methods outlined in Schemes 1 and 2 and in the Examples from compounds of Formula (9) wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom. Preferred among Formula (9) compounds when a nitrogen is present are those wherein A is nitrogen.
Prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (k) and Compound (s), are novel intermediates of Formula (c): 
wherein R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (k) and Compound (s), are novel intermediates of the formula: 
wherein R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (k), are novel intermediates of Formula (d): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a), R6 is OH or a protected OH and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (k), are novel intermediates of Formula (e): 
wherein R3 and R4 are as described in Formula (I), Xc is as described above, R is as described in Formula (a) and R6 is OH or a protected OH.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (k), are novel intermediates of Formula (f): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or a protected OH.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (k), are novel intermediates of Formula (g): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or a protected OH.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (k), are novel intermediates of Formula (h): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or a protected OH.
Prepared in synthesizing the indane carboxylates of Formula (2), preferably Compound (k), are novel racemic intermediates of Formula (27): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or a protected OH.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (k) and Compound (s), are novel intermediates of Formula (i): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (s), are novel intermediates of Formula (1): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a), R6 is OH or a protected OH and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also in synthesizing the indane carboxylates of Formula (18), preferably Compound (s), are novel intermediates of Formula (m): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or a protected OH.
Also in synthesizing the indane carboxylates of Formula (18), preferably Compound (s), are novel intermediates of Formula (n): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or a protected OH.
Also in synthesizing the indane carboxylates of Formula (18), preferably Compound (s), are novel intermediates of Formula (o): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or a protected OH.
Also in synthesizing the indane carboxylates of Formula (18), preferably Compound (s), are novel intermediates of Formula (p): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or a protected OH.
Also in synthesizing the indane carboxylates of Formula (2), preferably Compound (s), are novel racemic intermediates of Formula (28): 
wherein R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or a protected OH.
Also in synthesizing the indane carboxylates of Formula (18), preferably Compound (s), are novel intermediates of Formula (q): 
wherein R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are novel intermediates of Formula (10): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is as described in Formula (a).
Prepared in synthesizing the cyclopentano[b]pyridine derivatives of Formula (19) are intermediates of Formula (10) where three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is as described in Formula (a).
Prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are novel intermediates of Formula (11): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Prepared in synthesizing the cyclopentano[b]pyridine derivatives of Formula (19) are intermediates of Formula (11) where three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are novel intermediates of the Formula: 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Prepared in synthesizing the cyclopentano[b]pyridine derivatives of Formula (19) are intermediates of the preceding compound where three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (12): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1), R is as described in Formula (a), R6 is OH or protected OH and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (13): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, Xc is as described above, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (14): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, Xc is as described above, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (15): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (16): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel racemic intermediates of Formula (29): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (20): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (21): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1), R is as described in Formula (a), R6 is OH or protected OH and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (22): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, Xc is as described above, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (23): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, Xc is as described above, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (24): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (25): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel racemic intermediates of Formula (30): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R6 is OH or protected OH.
Also prepared in synthesizing the cyclopentano[xcex2]pyridine derivatives of Formula (19) are the novel intermediates of Formula (26): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Prepared in synthesizing the compounds of this invention are novel intermediates of the predominantly optically pure compound: 
Prepared in synthesizing the compounds of this invention are novel intermediates of the predominantly optically pure compound: 
All of the starting materials and reagents used herein are known and readily available or can be easily made from known and readily available reagents.
For example, compound (t) is prepared according to the following steps (as used below R3 and R4 are as described in Formula (1)):
a) an appropriately substituted 2-Bromo-5-methoxyphenol, prepared by methods such as described in de Paulis, et al. J. Med. Chem., 28, 1236 (1985), is treated with benzyl bromide and potassium carbonate to form the compound 
b) treating the product of step a) with magnesium in tetrahydrofuran to form the compound 
For example, compound (v) is prepared according to the following steps:
c) treating an appropriately substituted 2-Bromo-5-methoxyphenol from step a) above with ethylene carbonate and potassium carbonate in toluene to form the compound 
d) treating the product of step c) with potassium carbonate and benzyl chloride in N, N-dimethylformamide to form compound 
e) treating the product of step d) with magnesium in tetrahydrofuran to form compound 
For example, the most preferred compound (u) is prepared according to the following steps:
e) commercially available (1R, 2S)-(xe2x88x92)-ephedrine hydrochloride is reacted with urea and heat to form the compound 
f) treating the product of step e) with acroyl chloride in the presence of base to form compound (u). Preferably, the product of step e) is reacted in the presence of 3-chloropropionyl chloride and a base to form the predominantly optically pure compound (u) 